Pyrazolopyrimidine derivatives as NIK inhibitors

Abstract

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.

The invention claimed is: 
     
       1. A method of treating cancer in a warm-blooded animal which comprises administering to the said animal an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a tautomer or a stereoisomeric form thereof, wherein 
         R 1  is selected from the group of hydrogen; C 1-4 alkyl; and C 1-4 alkyl substituted with one or more fluoro substituents; 
         R 2  is selected from the group of hydrogen; C 1-4 alkyl; C 1-4 alkyl substituted with one or more fluoro substituents; C 3-6 cycloalkyl; and Het 1 ; 
         or R 1  and R 2  together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; 
         Het 1  is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl and pyrimidinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkyl substituted with one or more fluoro substituents, and C 1-4 alkyloxy substituted with one or more fluoro substituents; 
         X is N or CR 9 ; 
         R 9  is selected from hydrogen and halogen; 
         R 3  is selected from the group of hydrogen; halogen; cyano; C 3-6 cycloalkyl; C 1-6 alkyl; Het 4 ; C 1-6 alkyl substituted with one or more fluoro substituents; —OC 1-6 alkyl; 
         —OC 1-6 alkyl substituted with one or more fluoro substituents; and C 1-6 alkyl substituted with one substituent selected from —NR 3a R 3b  and —OC 1-4 alkyl; 
         Het 4  is a heteroaryl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, piperazinyl, morpholinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C 1-4 alkyl, —OC 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 alkyl substituted with one or more fluoro substituents; 
         R 3a  and R 3b  are each independently selected from hydrogen and C 1-4 alkyl; 
         R 4  is hydrogen; 
         R 5  is selected from the group of hydrogen; cyano; C 1-4 alkyl; C 1-4 alkyl substituted with one or more fluoro substituents; C 1-4 alkyl substituted with one substituent selected from the group of —NR 5a R 5b , —OC 1-4 alkyl, and Het 5 ; 
         R 5a  and R 5b  are each independently selected from the group of hydrogen and C 1-4 alkyl; 
         Het 5  is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C 1-4 alkyl, —OC 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 alkyl substituted with one or more fluoro substituents; 
         R 6  is selected from the group of hydrogen; Het 2 ; R 8 ; C 1-6 alkyl optionally substituted with one Het 3 ; and C 2-6 alkyl substituted with one or more substituents independently selected from the group of fluoro, NR 6a R 6b , and —OR 6c ; 
         R 6a  and R 6b  and R 6c  are each independently selected from hydrogen and C 1-6 alkyl; 
         Het 2  is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C 1-4 alkyl, —OC 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkyl substituted with one —OC 1-4 alkyl, C 1-4 alkyl substituted with one C 3-6 cycloalkyl, 
         and C 1-4 alkyl substituted with one or more fluoro substituents; 
         Het 3  is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C 1-4 alkyl, —OC 1-4 alkyl, C 3-6 cycloalkyl, 
         C 1-4 alkyl substituted with one —OC 1-4 alkyl, 
         C 1-4 alkyl substituted with one C 3-6 cycloalkyl, 
         and C 1-4 alkyl substituted with one or more fluoro substituents; 
         R 8  is C 3-6 cycloalkyl optionally substituted with one or two substituents independently selected from fluoro, C 1-4 alkyl, —OC 1-4 alkyl, C 1-4 alkyl substituted with one —OC 1-4 alkyl, and C 1-4 alkyl substituted with one or more fluoro substituents; 
         R 7  is selected from the group of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-4 alkyl substituted with one —OC 1-4 alkyl; 
         or a pharmaceutically acceptable addition salt, or a solvate thereof. 
       
     
     
       2. The method according to  claim 1 , wherein
 R 1  is selected from the group of hydrogen; C 1-4 alkyl; and C 1-4 alkyl substituted with one or more fluoro substituents; 
 R 2  is selected from the group of C 1-4 alkyl; C 1-4 alkyl substituted with one or more fluoro substituents; C 3-6 cycloalkyl; and Het 1 ; 
 or R 1  and R 2  together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; 
 Het 1  is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl and pyrimidinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkyl substituted with one or more fluoro substituents, and C 1-4 alkyloxy substituted with one or more fluoro substituents; 
 X is N or CR 9 ; 
 R 9  is selected from hydrogen and halogen; 
 R 3  is selected from the group of hydrogen; halogen; cyano; C 3-6 cycloalkyl; C 1-6 alkyl; C 1-6 alkyl substituted with one or more fluoro substituents; —OC 1-6 alkyl; —OC 1-6 alkyl substituted with one or more fluoro substituents; and C 1-6 alkyl substituted with one substituent selected from —NR 3a R 3b  and —OC 1-4 alkyl; 
 R 3a  and R 3b  are each independently selected from hydrogen and C 1-4 alkyl; 
 R 4  is hydrogen; 
 R 5  is selected from the group of hydrogen; cyano; C 1-4 alkyl; C 1-4 alkyl substituted with one or more fluoro substituents; C 1-4 alkyl substituted with one substituent selected from the group of —NR 5a R 5b , and —OC 1-4 alkyl; 
 R 5a  and R 5b  are each independently selected from the group of hydrogen and C 1-4 alkyl; 
 R 6  is selected from the group of hydrogen; Het 2 ; R 8 ; C 1-6 alkyl optionally substituted with one Het 3 ; and C 2-6 alkyl substituted with one or more substituents independently selected from the group of fluoro, —NR 6a R 6b , and —OR 6c ; 
 R 6a , R 6b  and R 6c  are each independently selected from hydrogen and C 1-6 alkyl; 
 Het 2  is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C 1-4 alkyl, —OC 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkyl substituted with one —OC 1-4 alkyl, C 1-4 alkyl substituted with one C 3-6 cycloalkyl, 
 and C 1-4 alkyl substituted with one or more fluoro substituents; 
 Het 3  is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C 1-4 alkyl, —OC 1-4 alkyl, C 3-6 cycloalkyl, 
 C 1-4 alkyl substituted with one —OC 1-4 alkyl, 
 C 1-4 alkyl substituted with one C 3-6 cycloalkyl, 
 and C 1-4 alkyl substituted with one or more fluoro substituents; 
 R 8  is C 3-6 cycloalkyl optionally substituted with one or two substituents independently selected from fluoro, C 1-4 alkyl, —OC 1-4 alkyl, C 1-4 alkyl substituted with one —OC 1-4 alkyl, and C 1-4 alkyl substituted with one or more fluoro substituents; 
 R 7  is selected from the group of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-4 alkyl substituted with one —OC 1-4 alkyl. 
 
     
     
       3. The method according to  claim 1 , wherein
 R 1  is C 1-4 alkyl; 
 R 2  is selected from the group of C 1-4 alkyl; and C 3-6 cycloalkyl; 
 X is N or CR 9 ; 
 R 9  is halogen; in particular fluoro; 
 R 3  is hydrogen; 
 R 4  is hydrogen; 
 R 5  is hydrogen; 
 R 6  is selected from the group of Het 2 ; and C 2-6 alkyl substituted with one —OR 6c ; 
 R 6c  is C 1-6 alkyl; 
 Het 2  is a heterocyclyl, bound through any available carbon atom, selected from the group of pyrrolidinyl, and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkyl substituted with one C 3-6 cycloalkyl; 
 R 7  is selected from the group of C 1-6 alkyl, and C 3-6 cycloalkyl. 
 
     
     
       4. The method according to  claim 1 , wherein
 R 3  is hydrogen; and R 5  is hydrogen. 
 
     
     
       5. The method according to  claim 1 ,
 R 6  is selected from the group of Het 2 ; and C 2-6 alkyl substituted with one —OR 6c . 
 
     
     
       6. The method according to  claim 5 , wherein R 6  is selected from the group of 
       
         
           
           
               
               
           
         
       
     
     
       7. The method according to  claims 1  to  6 ,
 R 1  is selected from the group of C 1-4 alkyl; 
 R 2  is selected from the group of C 1-4 alkyl; C 1-4 alkyl substituted with one or more fluoro substituents; C 3-6 cycloalkyl; and Het 1 ; 
 or R 1  and R 2  together with the carbon atom to which they are attached form a C 3-6 cycloalkyl. 
 
     
     
       8. The method according to  claims 1  to  6 , wherein X is N. 
     
     
       9. The method according to  claims 1  to  6 , wherein X is CR 9 . 
     
     
       10. The method according to  claim 1 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
         tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof. 
       
     
     
       11. The method according to  claims 1  to  6 , wherein the compound is in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier or diluent. 
     
     
       12. The method according to  claim 10 , wherein the compound is in a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier or diluent.